Although a variety of delivery systems are being developed for different routes of administration like the oral, parenteral, nasal and transdermal, the oral route remains attractive for drug delivery because this mode of administration is an easy, convenient, noninvasive and familiar method of drug delivery. The common oral dosage forms include: liquid mixtures like solutions, suspensions, solid dosage forms like tablets and capsules and liquid filled capsules etc. The solid dosage forms are further modified depending on the therapeutic action desired, like controlled, extended or delayed release. However, patients at the extremes of age, such as children and the elderly, often experience difficulty in swallowing solid oral dosages forms. For these patients the drugs are mostly provided in liquid dosage forms such as solutions, emulsions and suspensions. These dosage forms usually lead to perceptible exposure of the active drug ingredient to taste buds and this is a very serious problem when the drug has an extremely unpleasant or bitter taste.
The bitter taste of the drugs, which are orally administered, is disadvantageous in several aspects Taste is an important parameter governing the compliance. The disagreeable taste of drugs causes difficulties in swallowing or causes patients to avoid their medication thereby resulting in low compliance of patients. Conventional taste masking techniques such as use of sweeteners, amino acids, flavoring agents are often unsuccessful in masking the taste of the highly bitter drugs like quinine, barberin, etoncoxib, antibiotics like levofloxacin, ofloxacin, sparfloxacin, ciprofloxacin, celbroxime axetil, erythromycin and clarithromycin. Thus taste-masking technologies are considered important and developed by many researchers
Taste masking is a major problem when the drugs are extremely unpleasant and bitter and this problem is not restricted to the liquid oral compositions like solutions, dry syrups and suspensions but may also be encountered during the formulation of chewable tablets or dispersible tablets wherein these dosage forms usually lead to perceptible exposure of active ingredient to taste buds Depending on the type of dosage form, various methods have been employed to overcome the unpleasant taste and bitterness of the drug. Various methods for taste masking have been tried earlier, which include use of ion exchange resins, complexation of bitter drugs with pharmaceutically acceptable excipients and coating of drugs by lipids and various polymeric materials. Some of the highly bitter drugs are formulated using lipids.
U.S. Pat. No. 4,797,288 discloses a novel drug delivery system based on the hydrophobic matrix coating the core, such that the coating delays the hydration of the core. The delivery system comprises of dry drug particles designed either for chewing or swallowing. The hydrophobic matrix coating delaying the hydration of core comprised of about 200-400% by weight of the drug. The hydrophobic material had a melting point in the range of 25-100° C. The delivery system comprised of 61-95% by weight of fatty acid
GB Patent 1323161 discloses coating of acetoxymethyl benzylpenicillinate using lipids having a melting point of not more than 95° C. The coating of the lipid is achieved by spray congealing method. The coated powder is reconstituted at a pH of 6.5. The composition protects penicillin from moisture and also masks the bitter taste. However the use of lipids alone tends to delay the release of the drug owing to the hydrophobic nature of the lipids.
GB Patent 2081092 discloses use of waxy materials and high molecular weight water swellable materials. The water swellable material is added to improve dissolution, which helps in increasing the absorption of the drug. However the use of water swelling materials alone with lipids in compositions is of limited use since these compositions would tend to leach the drugs in the aqueous media used for reconstitution of dry syrups or also in suspensions.
U.S. Pat. No. 5,405,617 discloses a solve-it-less method for preparation of the taste-masked composition involving spray congealing of molten stearyl stearate and admixing an active pharmaceutical therewith.
U.S. Pat. No. 4,865,851 discloses a method for taste masking highly bitter 1 acetoxy ethyl ester of cefuroxime in particulate form, by coating with an integral coating of lipid or a mixture of lipids to mask the taste. Coated particles are incorporated in aqueous suspensions The lipids used are insoluble in water but are dispersed or dissolved in gastro-intestinal fluid The lipids used in the composition for taste masking are in the range of 95-10% and cefuroxime axetil is in the range of 5-90%. The preferred range of lipid is 90-70% and cefuroxime axetil is 10-30% The examples disclosed in the patent show a drug to lipid ratio of 1:4 and above
Robson et al. (H J. Robson, D Q. M Craig, D. Deutsch, International Journal to Pharmaceutics, 190, 1999, 183-192) have studied the dissolution of stearic acid coated cefuroxime axetil microspheres in distilled water and Sorensen modified butter pH 5.9, 7 and pH 8. The study indicated that the release of the drug from stearic acid coated cefuroxime axetil microspheres would increase on reaching the intestine. The coating helped in taste masking of cefuroxime axetil. Robson et al. (H. J. Robson, D. Q. M. Craig, D. Deutsch, International Journal of Pharmaceutics 195, 2000, 137-145) have also disclosed the influence of buffer composition on the release of the cefuroxime axetil from stearic acid coated cefuroxime axetil microspheres The buffers studied included the Sorensen modified phosphate buffer, Citrate phosphate buffer, boric acid buffer and the phosphate buffer mixed, all with the pH range of 7 according to the pharmaceutical codex 1994. The study shows effect of the pH and concentration of the sodium ions on release mechanism. The interaction of the stearic acid with buffer media containing sodium ions is effective for the release mechanism.
In the above disclosures release of cefuroxime axetil was studied in basic media. Dantzig et al (Anne H. Dantzig, Dale C Duckworth, Linda B. Tabas, Biochimica et Biophysica Acta 1191, 1994, 7-13) show that cefuroxime axetil is hydrolyzed to cefuroxime in the intestinal lumen by the esterases reducing the cefuroxime axetil concentration in the lumen, and resulting in reduced absorption, leading to low bioavailability of Cefuroxime axetil in humans. Hence formulations of drugs like cefuroxime axetil should be such that they release the drug in the upper gastric region rather than at the intestinal pH. Cefuroxime axetil already has a low bioavailability of 32-50% and hence further reduction in the bioavailability due to the formulation aspects should be minimized.
U.S. Pat. No. 4,897,270 discloses film-coated tablets of cefuroxime axetil to taste mask the bitter drug such that the film coat ruptures in few seconds and tablet disintegrates immediately. This preparation is useful for improving bioavailability of cefuroxime axetil. It is taught that cefuroxime axetil, once in contact with aqueous medium, forms a gelatinous mass The gelling effect is temperature dependent and occurs at temperatures of −37° C., i.e. at the physiological temperature at which disintegration of orally administered tablets, takes place Further, it is further taught that a tablet having conventional film coat containing cefuroxime axetil in the core, when orally administered results in gelation of drug due to slow permeation of moisture across the film coat. Gel formation leads to poor disintegration of tablet core and hence to poor dissolution, absorption and bioavailability of cefuroxime axetil. Drugs like cefuroxime axetil should therefore be so formulated that the compositions release the drug immediately in the gastric region without slow permeation of the buffer in coating material. It is further taught that coating material for cefuroxime axetil should be such that it releases the drug immediately before gelling occurs
U.S. Pat. No. 5,972,373 discloses the taste masking pharmaceutical compositions, which offer good bioavailability. The composition has a high polymer consisting of polyvinylacetal diethylaminoacetate, aminoalkylmethacrylate copolymer Eudragit E soluble in the stomach and a monoglyceride glyceryl monostearate used for taste masking. Such coating compositions would be of use for drugs such as cefuroxime axetil, which are better absorbed from the upper gastric region. However, cefuroxime axetil shows negative interaction with a polymer based on aminoalkylmethacrylate copolymer like Eudragit E.
Alonso et al (M. J Alonso, M. L. Lorenzo-Lamosa, M. Cuna, J. L. Vila-Jato and D. Torres, Journal of Microencapsulation, 1997, Volume 14, No 5, 607-616) studied encapsulation of cefuroxime axetil, a highly bitter drug, in pH sensitive acrylic microspheres in order to formulate a suspension dosage from. The study shows that cationic polymer Eudragit E (polymer containing dimethyl amino ethyl methacrylate) showed negative interaction with cefuroxime axetil.
U.S. Pat. No. 4,132,753 discloses a process for controlled release of medicament from a composition comprising wax like materials and having a melting point between 30-100° C. The lipid medicament mixture is agitated continuously at a temperature at which tie wax like material melts and the medicament powder sinks into the molten surfaces of the waxy material Coated granules were obtained by cooling molten mass followed by sizing. Wax like materials disclosed include glyceryl monostearate, hydrogenated fat and waxy aliphatic alcohol. U.S. Pat. No. 6,589,955 discloses a taste masked pediatric formulation of gatifloxacin. The taste masked co-precipitate of garifloxacin is formed with fatty acids like stearic acid or palmitic acid, the ratio of gatifloxacin to fatty acid being in a range of 1:1.8 to 1:2.3. The preferred ratio is 1:2.1. U.S. Pat. No. 6,156,339, discloses a process for preparation of a taste masked, solid oral rapidly disintegrating dosage form comprising water dispersible carrier, filler, pharmaceutical active and a lipid such that the pharmaceutical active is in association with the lipid Weight ratio of pharmaceutically active substance to lipid is in the range of 1:1 to 1:10.
Japanese Patent Application 2002138034 discloses a chewable tablet containing a bitter anitihistaminic drug, Chlorpheniramine maleate and fatty aced viz; stearic acid to mask the taste The composition contains fatty acid in the range of 0.5 pts wt to less than 3 pts. wt. of fatty acid per 1 pt. wt of the drug.
A chewable tablet with a medicament coated by lipid material is disclosed in French Patent 2784895 Lipid materials melting in a range of 37-75° C. are used The patent discloses 10%, preferably 2-5% or lipid being used for coating of the drug.
The lipid materials used in formulations like the crunchable/chewable tablets or granules for taste masking applications lead to the rapid release of the drug on fracturing of the lipid coat during the mastication, however this would lead to the perception of bitter taste.
U.S. Pat. No. 6,485,742 discloses coating of hydrophilic core material comprising vitamins, by drop wise addition of the molten lipid on a fluidized core material such that the molten lipid solidifies and forms a coat on the core material. Coating by lipid material masks the unpleasant flavor of the vitamin. The coating material is used in the range of 0.1 to 30% w/w of the total coated material. PCT International Application WO 00/61119 discloses a process for microencapsulation of a medicament by mixing the medicament with a coating agent, which is melted and kept under stirring. The melted material is cooled under stirring to yield the microcapsules.
U.S. Pat. No. 4,837,381 discloses a slow release microsphere preparation of a wax or fat containing the biologically active protein or peptide The invention discloses the use of 30-95% w/w of the fat or wax and 2-70% of the protein or peptide in the microsphere preparation.
Microspheres prepared by thermoforming of compositions containing pharmaceutical active in a range of 5-90%, 10-90% of glyceryl monostearate, and 2-15% of polyethylene glycol and glyceryl palmitostearate, are disclosed in the U.S. Pat. No. 6,117,452.
Japanese Patent Application 2001288117 discloses taste masking of oral preparation of drug rebamipide with fatty acid glycerol esters optionally with easily water-soluble substances. Water soluble or swelling substances are used to enhance release of the drug from lipid matrix. The use of water-soluble substances along with lipids limits their use in liquid oral preparation.
Pharmaceutical compositions with improved taste are disclosed in PCT International Application WO 00/06122. The drug is dispersed in fatty acid ester of glycerol base, 1.5 to 15 parts by weight based on 1 part of the drug. The fatty acid coated drug particles are further coated by water-soluble, water-insoluble or gastric soluble or an enteric polymer.
A substantially tasteless pharmaceutical delivery system is disclosed in EP 0670716. The delivery system comprises an active ingredient, a matrix of wax core material having a melting point in the range 50-200° C. and a hydrophobic polymer The amount of hydrophobic material present in the delivery system is 3-10% by weight of the matrix and the amount of the wax core present in the matrix is 15-85% by weight of the matrix.
Grains for oral administration obtained by spray solidification, which provide excellent taste-masking or bitter drugs, are disclosed in PCT International Application WO 00/18372 The grains contain a drug with unpleasant taste and a lipid carrier having melting point of 40 to 120° C. along with a polymer used to mask the unpleasant taste. The polymer used in combination with the lipid is either an enteric polymer or a gastric polymer.
PCT International Application WO 03/059349 discloses oral fast dispersing dosage form comprising microparticles for enhancing the bioavailability. The microparticles contain the drug zolpidem, fatty acids as spheronization aids like monoglycerides solubility enhancer like macrogol and the polymer coat to taste mask the product.
U.S. Patent Application Ser. No. 2004091536, discloses granules for dry reconstitutable telithromycin suspension comprising of the core of telithromycin and waxy material coated in succession by lipid and polymer coating twice and another coat containing optionally a lipid with the polymer
Matrices containing the bitter drug clarithromycin, glycerol fatty acid ester or stearyl alcohol and polymer selected from hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S are disclosed in PCT International Application WO 01/91761. The matrices provide oral formulations free of the bitter taste of clarithromycin.
The following patents and patent applications disclose the use of lipids alone or lipids with other inactives like polymers in pharmaceutical compositions of the drugs: WO 02/72072; U.S. Pat. No. 4,880,634, U.S. Pat. No. 5,571,533; U.S. Pat. No. 5,169,645, U.S. Pat. No. 6,086,920, WO 99/32092; U.S. Pat. No. 5,891,476, EP 0855183.
Lipids are associated with properties like water repellency, non-toxicity and freedom from objectionable odor and color and they impart a smooth texture to the compositions. These properties make the lipids are good candidates for the taste masking applications. However fatty acids do exhibit good film forming hence integral coatings with lipids alone need larger amount of lipids since the medicament has to be dispersed completely in the lipid matrix. The techniques like the melt granulation and spray congealing also need large amount of the molten lipids since the drug is required to be dispersed within the lipid matrix.
Lipids are hydrophobic in nature and so the release of the medicament is greatly impaired when lipids are used in higher amounts. Many formulations disclosed above employ polymers in combination with the lipids to accelerate the release of the drug. The use of water swelling or soluble polymers along with lipids provide immediate release of the drugs as desired but cannot provide the desired taste masking effect, especially in case of the liquid oral compositions or granules for reconstitution. The use of pH independent polymers like ethyl cellulose in combination with lipids for taste masking provides compositions which prevent the leaching of the drug in the surrounding aqueous media as in case of liquid orals but the drug release is delayed on ingestion. Similarly the compositions employing enteric polymers in combination with lipids tend to delay the drug release till they reach the intestine.
Some of the patent applications disclosed above, use gastric soluble polymer Eudragit E in combination with the lipids, which provide an immediate release of the drug and also the taste masking effect However Eudragit E shows a swelling up to pH 5.5 exhibits an interaction with certain drugs like Cefuroxime axetil.
Hence there is a need to develop formulation such that the amount of the total polymer required for the taste masking application is reduced and yet the composition delivers substantial amount of the drug in the gastric region without delay. Further the polymer should be such that it provides for a wider range of pH, for reconstitution of taste masked granules.
We have now discovered that the pH sensitive polymer disclosed and claimed in our co-pending applications PCT/IN03/00390 and PCT/IN03/00392, when used in combination with lipids, such as fatty acids, fatty acid esters and fatty alcohols for coating of drugs show taste masking of bitter drugs at the pH of saliva. The amounts of polymer required to achieve effective taste masking are lower than in our co-pending patent applications PCT/IN03/00390, PCT/IN03/00392 and U.S. patent application Ser. No. 10/871,534. The amounts of lipids required to achieve taste masking are also significantly lower than those in U.S. Pat. No. 4,865,851 Further, the rates of release of drugs from lipid-polymer mixtures in this present invention are significantly higher than those, which can be attained from formulations based on lipids or mixtures of lipids, under identical conditions.